This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The basis of the proposed work is to ask and answer questions in the arena of selective control of proteolytic action in parasitic disease. Our goal is to understand the function and regulation of proteolytic enzymes and to use structural biology to guide the design of potent, specific inhibitors. To achieve this, we use biochemical and structural biology technologies ? including high resolution x-ray crystallography. Targets under study include those pertinent to the goal of designing small molecule inhibitors to be optimized to new therapeutics for parasitic infection and are derived from the following organisms: cruzain and cruzipain 2, from Trypanosoma cruzi, TbCatB from Trypanosoma brucei rhodesiense, falcipain 3 from Plasmodium falciparum, EhCP4 from Entomeba histolytica and GlCP from Giardia lamblia. The diseases caused by these agents are, respectively, Chagas? disease, Human African Trypanosomiasis, malaria, amoebic colitis and giardiasis.